Factors Associated With Racial and Ethnic Disparities in Locally Advanced Rectal Cancer Outcomes

Key Points Question Do social determinants of health and demographic, clinical, and pathologic factors account for the racial and ethnic disparities observed among patients treated with neoadjuvant therapy and surgery for locally advanced rectal cancer (LARC)? Findings In this cohort study of 34 500 patients, treatment outcomes for LARC were less favorable for Hispanic and non-Hispanic Black patients than for non-Hispanic White patients. After accounting for all study variables, non-Hispanic Black race remained independently associated with a less favorable treatment response. Meaning These findings suggest that racial and ethnic disparities in LARC treatment outcomes may be multifactorial, with an independent association with non-Hispanic Black race, suggesting unidentified biological variables or social determinants of health that warrant exploration.


Introduction
In approximately 60% of cases, rectal cancer is locally advanced (stage II or III) at diagnosis and is treated under current guidelines with chemoradiotherapy and surgery. 1,24][5][6][7] Demographic data reveal that young Black and Hispanic patients account for much of this trend. 80][11][12][13][14] Black patients with LARC, in particular, have been shown to be approximately 45% more likely to die of their disease than White patients. 15veral potential contributors to racial disparities in treatment outcomes are well-established.
For example, Black patients are less likely to receive adjuvant chemotherapy or radiotherapy for rectal cancer than White patients, even after controlling for age, clinical stage at diagnosis, and comorbid disease. 11,16Large-scale studies of LARC 17,18 have also established the role of pathologic factors-tumor stage, lymph node status, and circumferential resection margin-in determining overall LARC survival, suggesting a potential role for these variables in any investigation of disparate outcomes.More recently, retrospective studies of LARC 19,20 have demonstrated the contribution to racial disparities of social determinants of health (SDOH), including educational level, income, marital status, geographic location, and access to treatment.Indeed, racial and ethnic minority individuals have been significantly underrepresented in clinical trials, and 43% of US cancer studies omit altogether the classification of outcome data by racial groups. 21,220][31][32][33][34][35] As an illustration, a recent study of patients with colorectal cancer undergoing surgery 36 demonstrated decreased 1-and 5-year survival for Asian, Hispanic, non-Hispanic Black, and Pacific Islander patient populations compared with White patients.This disparity persisted after adjustment for multiple demographic variables, including insurance status and marital status, with Hispanic patients exhibiting the worst survival decrement. 36However, multiple additional factors are evidently at work.Herein, we have undertaken an analysis using a focused inventory of SDOH in addition to prognostically relevant demographic, clinical, and pathologic data within a contemporary National Cancer Database (NCDB) cohort.Accordingly, we have focused on the pathologic complete response (pCR), which is considered a favorable outcome and an important prognostic factor for patients with rectal cancer, 37,38 as a key measure of disparate outcomes for non-Hispanic Black and Hispanic patients with LARC who undergo neoadjuvant therapy and surgery.and treated with neoadjuvant therapy followed by surgical resection (Figure 1).0][41]

Outcome Measures
Pathologic complete response served as the primary outcome, defined to be a T0 N0 surgical specimen obtained following neoadjuvant therapy.3][44][45][46] Secondary outcomes were tumor downstaging and pN0 status.8][49] Pathologic N0 status was defined as a lymph node-negative surgical specimen and is associated with a lower risk of recurrence and improved survival. 48,49mographic, Clinical, and Pathologic Covariates and SDOH [LAR] or abdominoperineal resection [APR]), dose of radiation (<45.0,45.0-50.4,or >50.4 Gy), neoadjuvant chemotherapy (yes or no), surgical margins (positive or negative), tumor grade (1-4 or unknown), tumor stage (T0-T4), nodal stage (N0-N2), and race and ethnicity.To distinguish between staging at diagnosis and subsequent downstaging, we used the standard approach.We used the initial tumor staging and grade information provided in the NCDB data, 50,51

Statistical Analysis
Patients were categorized as Hispanic, non-Hispanic Black, or non-Hispanic White based on selfreported race and ethnicity.The demographic and clinical data for the 3 study groups were compared using analysis of variance and χ 2 tests, with additional pairwise tests.The response to neoadjuvant therapy was determined by the rates achieved for pCR, tumor downstaging, and pN0 status.
Multivariate logistic regression models were used to investigate the association between race and ethnicity groups adjusting for SDOH and demographic and clinical factors.To account for the correlation within facilities, generalized estimating equations with robust SEs were used.As a sensitivity analysis, we conducted additional multivariate analysis (MVA) adjusting for the time between end of radiotherapy and surgery in the subset of the population where this time was known.
All tests were 2 sided, and P < .05 was considered significant.All computations were performed using SAS, version 9.4 (SAS Institute Inc).

Discussion
This examination of a large multiethnic and multiracial cohort of patients with LARC undergoing neoadjuvant therapy and surgery confirmed and expanded on previously reported findings of racial and ethnic disparities in treatment outcome.We observed that Hispanic and non-Hispanic Black patients had primary higher-stage tumors with greater nodal involvement.Additionally, both Hispanic and non-Hispanic Black patients achieved less tumor downstaging and pN0 status than non-Hispanic White patients.Non-Hispanic Black patients, however, demonstrated a lower rate of pCR than Hispanic and non-Hispanic White patients.Both Hispanic and non-Hispanic Black patients with LARC were more likely to be treated with APR than non-Hispanic White patients and were thus less likely to undergo sphincter-preserving surgery.Both Hispanic and non-Hispanic Black patients achieved less tumor downstaging and pN0 status than non-Hispanic White patients.Only non-Hispanic Black patients, however, demonstrated a lower rate of pCR and continued to demonstrate an association with downstaging and pN0 status in adjusted MVA models.Of note, a sensitivity analysis that additionally adjusted for the time between completion of radiotherapy and surgery in the study population showed that inclusion of these variables did not change the interpretation of our findings.
To better understand the association of SDOH with outcomes, multiple other variables were examined.In this study, Hispanic and non-Hispanic Black patients were both distinguished from non-Hispanic White patients by their younger age, their lower educational and income levels, their frequent residence in metropolitan areas, their greater reliance on low-volume treatment centers, and their lack of private insurance.Prior work 53,54 has consistently demonstrated the significant effect of insurance coverage on cancer outcomes.For instance, in an analysis conducted by Sineshaw et al 53 involving Black and White patients with colorectal cancer in the NCDB, insurance coverage played a pivotal role, accounting for approximately one-half of the survival disparities observed between Black and White patients.The importance of insurance coverage extends throughout the entire cancer care journey, from diagnosis to the entirety of the treatment continuum. 53In our findings, we observed that in some cases, the distinguishing features of the Hispanic and non-Hispanic Black groups bore no obvious relation to the observed unfavorable clinical outcomes.
A rural address, for example, has been associated with compromised health care access and reduced LARC survival. 20Urban areas, in contrast, are typically home to the high-volume centers that reportedly yield the highest rates of survival for LARC. 55In this study, Hispanic and non-Hispanic Black patients were found to live disproportionately in metropolitan areas but were more likely to be treated in low-volume centers, an anomaly that is perhaps due to transportation difficulties related to limited economic resources and/or lack of public transit to high-volume centers in residentially segregated areas. 27,29Low-volume centers often have limited resources that could influence clinical care.For instance, although APR and LAR procedures have been shown to be comparable with respect to local recurrence rates, 56 LAR is more frequently performed in higher-volume settings where surgeons are more experienced or have been trained in colorectal surgery. 57,58Thus, it is possible that SDOH measures in this study could help explain differences in cN0 status and downstaging between Hispanic and non-Hispanic White patients, but they did not fully attenuate the association among non-Hispanic Black race, downstaging, and pCR.
To our knowledge, this is the first study in LARC to examine the association of multiple SDOH and demographic, clinical, and pathologic factors known to be predictive factors for treatment response.It is noteworthy that non-Hispanic Black race remained associated with an unfavorable treatment outcome, even after adjustment for the large number of SDOH and demographic, clinical, and pathologic variables included in this analysis.Particularly for non-Hispanic Black patients, evidently undiscovered factors contribute to their disparate outcomes.The lower frequency of pCR observed for non-Hispanic Black patients with LARC is consistent with other studies [59][60][61][62][63][64] that have examined overall survival for non-Hispanic Black patients and reported (as is true for pCR) that patients who belong to ethnic and racial minority groups experience disproportionately unfavorable outcomes in terms of overall survival.Such reports provide a sound rationale for a follow-up to the current study that adopts overall survival as the primary outcome measure.Furthermore, the advanced stage and greater lymph node involvement observed in Hispanic and non-Hispanic Black patients raise questions about potential delays in diagnosis and their effect on the perceived surgical options at the time of diagnosis.Tumor location within the rectum may also play a role in these disparities.This suggests that improvements in cancer screening among these populations may be a viable strategy for diminishing the disparate treatment outcomes we observed for pN0 status and downstaging.Additionally, genetic differences associated with the non-Hispanic Black population are another potential undetected contributor to the observed disparities. 65As noted previously, investigation of genetic biomarkers has been impeded by underrepresentation of both Black and Hispanic patients in clinical studies and in major databases. 66Overall, while this study has underscored the persistence of disparities, particularly among non-Hispanic Black patients, it also emphasizes the urgent need for further investigations.Given our findings, any future study will need to follow the present one in considering the contribution of a wide range of demographic, socioeconomic, clinical, biological, and pathologic covariables.Ultimately, the goal is to enhance treatment outcomes for all patients, irrespective of their racial or ethnic backgrounds.

Limitations
Study limitations arise from the unavailability of comprehensive data on all SDOH, including the social and community context domain, and biological factors (eg, genetics) that can contribute to clinical outcomes.Additional limitations include the retrospective nature of database research and the exclusion of cases with missing first-line treatment, race and ethnicity, or survival data.Exploring the effect of short-vs long-course radiotherapy is an interesting avenue for future research, and it could provide valuable information regarding its role in influencing treatment outcomes and demographic disparities, though it was outside the scope of this study.Given our large sample size, there is a possibility of a type I error, which can result in statistically significant findings that may lack clinical relevance; thus, the results should be carefully interpreted.The availability of genetic ancestry information in addition to self-reported race and ethnicity coding would allow a more comprehensive understanding of the complex problem investigated and the role of biology.Even after adjustment for available social, clinical, and demographic variables, non-Hispanic Black patients were more likely to have a suboptimal response to therapy.8][69][70][71][72] Discrimination is challenging to capture in hospitalbased datasets and is another study limitation.8][69][70][71][72] We also recognize the intricate diversity and limitations inherent in the conventional racial and ethnic classifications used in this study.Selfreported race and ethnicity serve as oversimplified categorizations for multifaceted variations that encompass a range of intersecting factors such as ancestry and sociocultural influences. 73,74ditional possible explanations for the disparities in outcomes include either host or tumor factors that are associated with response to chemoradiotherapy.Not only are the clinical trials that define standard treatments composed overwhelmingly of White patients, but there are no widely available model systems to study this disease in Black patients.In future studies, it would be valuable to investigate potential disparities in LARC based on race and ethnicity by leveraging existing genomic data resources.

Conclusions
In this cohort study, Hispanic and non-Hispanic Black patients receiving neoadjuvant therapy for LARC achieved lower rates of tumor downstaging and pN0 status than non-Hispanic White patients.
For non-Hispanic Black patients only, pCR rates were also less than for non-Hispanic White patients.
In a comparison with non-Hispanic White patients, Hispanic and non-Hispanic Black patients were younger, with lower levels of education and income and less frequent coverage by private health insurance, and had tumors of higher stage with greater nodal involvement.Despite living in metropolitan areas, they tended to receive treatment in lower-volume centers where they disproportionately underwent APR rather than sphincter-preserving surgery.After controlling for all covariables affecting treatment outcome, non-Hispanic Black race remained independently associated with a reduced likelihood of a pCR.The results suggest that the racial and ethnic disparities in treatment outcomes for LARC are complexly determined, encompassing multiple socioeconomic, clinical, and pathologic variables as well as additional unknown variables-including possible biological and SDOH differences-that must be unraveled before racial and ethnic disparities can be overcome.

Methods Data Source and Study Sample Data
Racial and Ethnic Disparities in Locally Advanced Rectal Cancer Outcomes for patients with LARC were culled from the NCDB.All work was conducted from July 1, 2022, through December 31, 2023.Patients were eligible for the study if they were 18 years or older, diagnosed with T3 to T4 or N1 to N2 rectal cancer betweenJanuary 1, 2004, and December 31, 2017, JAMA Network Open.2024;7(2):e240044.doi:10.1001/jamanetworkopen.2024.0044(Reprinted) February 29, 2024 2/16 Downloaded from jamanetwork.comby guest on 03/06/2024 This study followed the reporting requirements of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement.In accordance with Fox Chase Cancer Center Institutional Review Board guidelines, interrogation of the deidentified NCDB was not considered human participant research and therefore did not require informed consent.

Table 1 .
Demographic, Clinical, and Pathologic Characteristics and Social Determinants of Health by Race and Ethnicity a (continued) a Unless otherwise indicated, data are expressed as No. (%) of patients.Percentages have been rounded and may not total 100.1.05]) were associated with the likelihood of a pCR.In sensitivity analyses adjusting for time between completion of radiotherapy and surgery, associations between race or ethnicity and neoadjuvant treatment outcomes were similar to those of our main analysis (eTables 1-3 in Supplement 2).